Rheumatism refers to any of several pathological conditions of the muscles, tendons, joints, bones, or nerves, characterized by discomfort and disability. It is estimated that over 100 rheumatic diseases affect the joints and other connective tissues of animals.
Arthritis is an autoimmune disease characterized by their symptoms such as pain, swelling and stiffness in the joints. The two major forms of arthritis in mammals are inflammatory arthritis such as rheumatoid arthritis (RA), and osteoarthritis (OA), a progressive, degenerative loss of cartilage often secondary to mechanical stress, aging, dysplastic conditions and/or injury. The symptoms of arthritis generally relate to arthrosis of spine, e.g., hallux rigidus, arthrosis psoriaticum and rheumatic arthritis.
Rheumatoid arthritis (RA) is a common autoimmune disease characterized by joint swelling, deformation and ultimately, destruction, culminating in severe physical disability. Rheumatic diseases include diseases of the muscles, tendons, joints, bones or sinews, which are generally characterized by inflammation and/or degeneration. Approximately 1 to 2% of the population suffer from rheumatoid arthritis, which is characterized by an imbalance in the immune system that causes an overproduction of pro-inflammatory cytokines, e.g., TNF-.alpha., IL-1 and a lack of anti-inflammatory cytokines, e.g., IL-10, Il-1. RA is characterized by synovial inflammation, which progresses to cartilage destruction, bone erosion and subsequent joint deformity. During the inflammatory process, polymorphonuclear cells, macrophages and lymphocytes are released. Activated T-lymphocytes produce cytotoxins and pro-inflammatory cytokines, while macrophages stimulate the release of the prostaglandins and cytotoxins. Vasoactive substances (histamine, kinins and prostaglandins) are released at the site of inflammation and cause edema, warmth, erythema and pain associated with inflamed joints.
Most of the current treatments are directed to the correction of immune aberration that supposedly drives the synovial cell proliferation and cartilage erosion. Present treatment of arthritis includes first line drugs for controlling pain and inflammation classified as non-steroidal anti-inflammatory drugs (NSAIDs), e.g., aspirin, ibuprofen, naproxen, etc. Secondary treatment of arthritis includes corticosteroids, slow acting antirheumatic drugs (SAARDs) or disease-modifying anti-rheumatic drugs (DMARDs), e.g., methotrexate, penicillinamine, cyclophosphamide, gold salts, azothipoprine, levamisole, etc.
The use of glucocorticoides and non-steroidal anti-inflammatory drugs (NSAIDs) in treating RA has been known for quite some time and are considered conservative treatment for RA. Corticosteroids, the synthetic versions of the body's cortisone hormone, are used to inhibit RA progression. They effectively reduce inflammation and suppress auto-immunity. The most commonly prescribed corticosteroids are prednisone and dexamthasone. Long-term use of dexamthasone, however, can produce such side effects as weight gain, rounding of the face, thinning of the skin and bone, acne, easy bruising, high blood pressure, and an increased risk of diabetes, infection and stomach ulcers. As a result, they are generally used only for short periods of time during acute flare-ups.
Among the disease-modifying anti-rheumatic drugs (DMARDs), methotrexate (MTX) became a benchmark agent for its efficacy and tolerability in the early phase of RA and the recent FDA approved leflunomide, an inhibitor of dihydro-orotate dehydrogenase, is known for its efficacy in treating RA, even though the specific mechanism of action of leflunomide is not yet known. However, most of the DMARDs have potential long-term side effects and toxicity. For example, the use of leflunomide may affect the lymphocyte function in vivo and in vitro.
Recently, another group of drugs called biological-response modifiers (BRMs) has also been developed for treatment of RA. The first group of BRMs approved for treatment of RA includes the antagonists to TNF-α, which work through binding to its receptor or directly binding to the TNF-α protein. However, BRM therapy, despite substantial efficacy and clinical improvement, entails high cost and hypersensitivity to the medications and infections due to TNF-α blockage.
Action mechanism of all of these drugs is based on suppression of inflammatory reaction. To our knowledge, no drugs have been developed for cartilage protection. Also, most of these drugs have various toxic, particularly cytotoxic, side effects. Thus, these drugs have limited advantages and their effects are mainly of short-term duration. The side effects of these drugs, e.g., gastric erosion which has adverse effects on kidneys and liver, dictate against their use over extended periods of time. Further, the drugs used at the present time are costly and have low benefit-risk ratios.
Thus, there exists a need for antiinflammatory, analgesic and antipyretic herbal-based therapeutics which are cost-effective, safe, and efficacious, and with less or no side effects, so that it can be used for over prolonged period of time.
Natural products derived from plants and animals have offered a vast reservoir of materials, which have potential pharmacological effects on humans, and have been the sources for effective drugs. Most of the natural products are non-toxic and relatively inexpensive. Some of the herbal products have demonstrated therapeutic effects in treating various diseases or disorders. According to the World Health Organization (WHO), 4 billion people, i.e., about 80% of the world population, use herbal medicines for some aspects of health-related treatments. A recent study on trends in alternative medicine use show that there is a 47.3% increase in visits to alternative medicine practitioners from 1990 to 1997, with 629 million of total visits, exceeding 386 million total visits to all US primary care physicians in 1997. Herbal medicines represent the fastest growing segment among all of alternative medicines.
Herbal medicines can be used as botanical drugs and/or dietary supplements.
Botanical Drug
A botanical drug consists of vegetable materials, which may include plant materials, algae, macroscopic fungi, or combinations thereof. A botanical drug product may be available as (but not limited to) a solution (e.g., tea), powder, tablet, capsule, elixir, topical, or injection. In August 2000, US FDA has published draft guidance for industry botanical drug products.
Dietary Supplement
US Congress defined the term “dietary supplement” in the Dietary Supplement Health and Education Act (DSHEA) of 1994. A dietary supplement is a product taken by mouth that contains a “dietary ingredient” intended to supplement the diet. The “dietary ingredients” in these products may include: vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites. Dietary supplements can also be extracts or concentrates, and may be found in many forms such as tablets, capsules, softgels, gelcaps, liquids, or powders. They can also be in other forms, such as a bar, but if they are, information on their label must not represent the product as a conventional food or a sole item of a meal or diet. Whatever their form may be, DSHEA places dietary supplements in a special category under the general umbrella of “foods,” not drugs, and requires that every supplement be labeled a dietary supplement.
Technical speaking, an herb is a small, non-woody (i.e., fleshy stemmed), annual or perennial seed-bearing plant in which all the aerial parts die at the end of each growing season. As the word is more generally used and as it is used herein, an herb is any plant or plant part which has a medicinal use. Thus, the seeds, leaves, stems, flowers, roots, berries, bark, or any other plant parts that are used for healing are considered to be an herb.
Herbal medicines have been used for treating various diseases of humans and animals in many different countries for a very long period of time (see, e.g., Kessler et al., The Doctor's Complete Guide to Healing Medicines, Berkley Health/Reference Books (1996); Mindell, supra). Herbal medicines are available in many forms, (including capsules, tablets, or coated tablets; pellets; extracts or tinctures; powders; fresh or dried plants or plant parts; prepared teas; juices; creams and ointments; essential oils; or, as combinations of any of these forms) and administered by various methods (including orally, rectally, parenterally, enterally, transdermally, intravenously, via feeding tubes, and topically). They are prepared by different methods (including crude powders, decocted herbs to refined, concentrated and standardized extracts).
The health benefit from taking herbs varies due to the quality of the products and the knowledge of consumers on the products. Some of the botanical drug products are required to be used under a physician's supervision, particularly those indicated for serious diseases, although the majority of herbal medicines are generally regarded as safe. It is estimated that approximately 50 percent of the thousands of drugs commonly used and prescribed today are either derived from a plant source or contain chemical imitations of a plant compound (Mindell, E. R., Earl Mindell 's Herb Bible, A Fireside Book (1992)).
A number of herbal compositions are known to be useful for treatment of various diseases and other health-related problems afflicting humans and animals. For example, U.S. Pat. No. 5,417,979 discloses a composition comprising a mixture of herbs, including species of Stephania and Glycyrrhiza, as well as their extracts, which is used as an appetite stimulant and for treatment of pain. Herbal compositions which include Glycyrrhiza uralensis have been found useful for treating eczema, psoriasis, pruritis and inflammatory reactions of the skin (U.S. Pat. No. 5,466,452). U.S. Pat. No. 5,595,743 discloses various herbs, such as licorice extract (Glycyrrhiza) and siegesbeckia, sophora, stemona and tetrandra herbs, which are useful for treatment of various mammalian diseases, including inflammation and rheumatoid arthritis. Ocular inflammation can be treated with the plant alkaloid tetrandrine (U.S. Pat. No. 5,627,195). In addition, U.S. Pat. No. 5,683,697 discloses a pharmaceutical composition having anti-inflammatory, anti-fever, expectorant or anti-tussive effect. The composition includes plants from Melia, Angepica, Dendrobium, Impatiens, Citrus, Loranthus, Celosia, Cynanchum and Glehnia. An herbal formulation comprising extracts of the roots, rhizomes, and/or vegetation of Alphinia, Smilax, Tinospora, Tribulus, Withania and Zingiber has been found having the effects of reducing or alleviating the symptoms associated with rheumatoid arthritis, osteoarthritis, reactive arthritis and reducing the production of proinflammatory cytokines (U.S. Pat. No. 5,683,698).
In the invention to be presented in the following sections, a herbal composition containing Radix Clematidis, Radix Angelicae Pubescentis, Rhizoma et Radix Notopterygii, Radix Saposhnikoviae, Radix Gentianae Macrophyllae are described. A herbal composition, further containing Radix Angelicae Sinensis, Rhizoma Chuanxiong, Cortex Eucommiae, and Radix Achyranthis Bidentatae, are described.
All the raw materials used for the complex herbal formulation are listed in the Chinese Pharmacopoeia. This herbal composition is particularly effective in treating and preventing inflammatory and rheumatic arthritic diseases in humans.